PT  - JOURNAL ARTICLE
AU  - Sophie Restituito
AU  - Latika Khatri
AU  - Ipe Ninan
AU  - Paul M. Mathews
AU  - Xin Liu
AU  - Richard J. Weinberg
AU  - Edward B. Ziff
TI  - Synaptic Autoregulation by Metalloproteases and γ-Secretase
AID  - 10.1523/JNEUROSCI.2513-11.2011
DP  - 2011 Aug 24
TA  - The Journal of Neuroscience
PG  - 12083--12093
VI  - 31
IP  - 34
4099  - http://www.jneurosci.org/content/31/34/12083.short
4100  - http://www.jneurosci.org/content/31/34/12083.full
SO  - J. Neurosci.2011 Aug 24; 31
AB  - The proteolytic machinery comprising metalloproteases and γ-secretase, an intramembrane aspartyl protease involved in Alzheimer's disease, cleaves several substrates in addition to the extensively studied amyloid precursor protein. Some of these substrates, such as N-cadherin, are synaptic proteins involved in synapse remodeling and maintenance. Here we show, in rats and mice, that metalloproteases and γ-secretase are physiologic regulators of synapses. Both proteases are synaptic, with γ-secretase tethered at the synapse by δ-catenin, a synaptic scaffolding protein that also binds to N-cadherin and, through scaffolds, to AMPA receptor and a metalloprotease. Activity-dependent proteolysis by metalloproteases and γ-secretase takes place at both sides of the synapse, with the metalloprotease cleavage being NMDA receptor-dependent. This proteolysis decreases levels of synaptic proteins and diminishes synaptic transmission. Our results suggest that activity-dependent substrate cleavage by synaptic metalloproteases and γ-secretase modifies synaptic transmission, providing a novel form of synaptic autoregulation.